Myocardin: new therapeutic agent in vascular disease?
Myocardin: new therapeutic agent in vascular disease?
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心肌素：血管疾病的新治疗剂？
DOI：
10.1161/atvbaha.113.302068
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Miano,JosephM
中科院分区：
文献类型：
--
作者：
Long,Xiaochun;Miano,JosephM
Long and Miano Myocardin and Vascular Injury 2285 functional CArG boxes, Talasila et al surveyed the genomic landscape around miR24 and miR29a for these important regulatory codes. miR24 and miR29a harbor CArG-like boxes; however, Talasila et al were unable to demonstrate binding of either MYOCD or SRF using a ChIP assay, indicating MYOCD induction of these microRNAs occurs in an unconventional manner.To formally demonstrate a link between MYOCD induction of miR24 and miR29a, PDGFRB expression, and VSMC migration, Talasila et al first used standard luciferase reporter experiments and qRT-PCR studies with antimiRs to validate the repressive action of miR24 and miR29a on PDGFRB expression. Next, they rescued MYOCD inhibition of PDGFRB expression and VSMC migration using antimiRs to both miR24 and miR29a. Importantly, overexpression of each microRNA was sufficient to inhibit VSMC migration in vitro. In vivo, vascular injury resulted in attenuated expression of miR29a consistent with reduced levels of MYOCD. Furthermore, there was a decrease in expression of miR24 and miR29a, as well as miR143/145, and an increase in PDGFRB in the injured carotid artery of heterozygous Myocd null mice. Collectively, these results would suggest that the inhibition of VSMC migration by MYOCD occurs, in part, through the induction of miR24 and miR29a and their repressive action on the PDGFRB transcript. It is likely that other events are occurring with MYOCD overexpression such as the induction of long noncoding RNAs that may directly or indirectly modulate PDGFRB expression levels. The results of Talasila et al are the first to document a potentially efficacious role for MYOCD in vascular injury responses. The question will be whether MYOCD can be harnessed and safely used as a new therapeutic modality for human vascular diseases. Several outstanding questions and challenges exist. First, we need additional tools to study MYOCD protein expression in a reliably consistent manner. Second, the role of MYOCD in other vascular disease models should be thoroughly assessed including atherosclerosis, hypertension, and transplant arteriopathy. Third, we need to fully define the transcriptome after MYOCD overexpression, including all long noncoding RNAs which already outnumber protein-coding genes and display increasingly diverse functions in the cell. 18 Fourth, because MYOCD is sufficient to orchestrate biochemical, structural, and physiological attributes of VSMCs, 19 strategic targeting of cells (whether through gene therapy or small molecule agonists of MYOCD) will be critical so as to minimize the reprogramming of other cell types that may be important in maintaining vascular homeostasis (eg, endothelial cells). Despite these limitations, the data from Talasila et al provide an important foundation for future work on MYOCD in the setting of vascular disease.
